QT lungo
Flavio Ribichini
Cardiologia
Università di Verona
01/10/2010 101/10/2010 2
Principi di base dell’ECG
01/10/2010 3
L'amperometro è uno strumento
per la misura dell'intensità di
corrente elettrica, che percorre una
sezione di un conduttore
Il galvanometro è uno strumento
che traduce una corrente elettrica
in una torsione meccanica.
ECG
01/10/2010 4
L'elettrocardiogramma
(ECG) è la registrazione
dell'attività elettrica del
cuore che si verifica nel
ciclo cardiaco.
’
Ciclo depolarizzazione
ripolarizzazione
01/10/2010 6
il prolungamento QT é correlato al blocco dei canali del
potassio, questi riducono la corrente di ripolarizzazione in
uscita e prolungano la durata del potenziale d’azione e
l’intervallo QT.
E il QT lungo?
01/10/2010 7
INTERVALLO QT: è la
distanza tra la prima
deflessione del QRS e la
fine dell’onda T.
IL QTc misura la durata
(tempo) diviso la radice
dell’intervallo RR in sec
Nota: il QT viene misurato in msec,
L’intervallo RR in sec,
quindi il QTc è una standardizzazione
della durata del QT per la FC
Valori di normalità del QT
01/10/2010 8
Un intervallo QT non corretto oltre 500
msec è usualmente considerato
ECG normale: esercizio 1
01/10/2010 91quadratino
piccolo 40 msec
1 quadrato grande
200 msec
1 quadrato grande e
3 piccoli:
200+120=320 msec
Esercizio 2
01/10/2010 103 quadrati
grandi da
200 msec
+
1quadratino
piccolo 40
msec
Esercizio 3
01/10/2010 113 quadrati
grandi =
600 msec
Numerosi sono i meccanismi con cui gli antipsicotici alterano
la conduzione cardiaca, quasi sempre gli antipsicotici
antagonizzano la componente rapida
del canale del
potassio Ikr.
Il canale del potassio IKr è codificato dal gene umano HERG
(human Ether-à-go-go Related Gene) e studi di tranfezione di
cellule del gene HERG mostrano un antagonismo diretto di
alcune sostanze tra cui
aloperidolo
(Suessbrich 1997)
sertindolo
(Rampe
D.1998)
clozapina
(Tie
H
2000),
tioridazina e clorpromazina
(Tie H 2001). Questo è il
meccanismo maggiormente implicato
nell’allungamento del
QT (William J 2006)
Il blocco del recettore IKr risulta dose dipendente (Drolet
1999, Tie H 2000)
Alcuni antipsicotici sembrano interferire anche con i canali del
sodio e del calcio (Shader 1999)
01/10/2010 13
L’inizio del problema…
01/10/2010 14
Non è chiaro l’effetto sul QTc a bassi dosaggi (5 mg die) o a
dosaggi moderati (5-20 mg die) (Fulop 1987, Czekalla 1961)
Segnalato allungamento del QTc e torsioni di punta per alti
dosaggi per os (>20 mg die) (Kriwisky 1990, Metzger 1993) o
in caso di sovradosaggio (Henderson 1991)
Alti dosaggi (>50 mg die) per via endovenosa si associano ad
un allungamento del QTc con casi descrtitti di torsioni di punta
(
Lawrence 1997, O’Brien 1999)
Per dosaggi endovenosi da 5-25 mg sono segnalati aumenti
del QTc a valori superiori a 500 ms (Hatta 2000)
Per somministrazione intramuscolare di una dose di 7.5 mg
seguita da dose di 10 mg è segnalato un aumento medio del
QTc di 15 ms.(Miceli JL 2002)
01/10/2010 15
Concetti pratici…
1.
La dose e la via di somministrazione ha un’importanza
nella possibile tossicità?
2.
E’ da preferire/evitare una via parenterale ad una via
orale?
3.
L’effetto degli antipsicotici sul QT è sinergico?
01/10/2010 16
Concetti pratici…
1.
La dose e la via di somministrazione hanno
un’importanza nella possibile tossicità?
SI
, la dose e le somministrazioni parenterali aumentano la
biodisponibilità di questi farmaci e quindi possono
causare un maggior blocco dei canali del K e maggior
allungamento del QT.
01/10/2010 17
Abstract
STUDY OBJECTIVE: To characterize the effect of oral ziprasidone and haloperidol on the corrected QT (QTc) interval under steady-state conditions. Design. Prospective, randomized, open-label, parallel-group study.
SETTING: Inpatient clinical research facility. Patients Fifty-nine adults (age range 25-59 yrs) with
schizophrenia or schizoaffective disorder who had no clinically significant abnormality on electrocardiogram (ECG) at screening. Intervention. During period 1 (days -10 to -4), antipsychotic and anticholinergic drugs were tapered. On the first day (day -3) of period 2, the drugs were discontinued, and placebo was given for the next 3 days (days -2 to 0). On the last day (day 0) of period 2, serial baseline ECGs were collected. During period 3 (days 1-16), patients received escalating oral doses of ziprasidone and haloperidol to reach steady state. Period 4 (days 17-19) allowed for study drug washout and initiation of outpatient antipsychotic therapy; safety assessments were also performed during this period.
MEASUREMENTS AND RESULTS: At each steady-state dose level, three ECGs and a serum or plasma sample were collected at the predicted time of peak exposure to the administered drug. Point estimates and 95% confidence intervals (CIs) were determined for the mean QTc interval at baseline and for the mean change from baseline in QTc at each steady-state dose level. Mean changes from baseline in the QTc interval (msec) for ziprasidone were 4.5 (95% CI 1.9-7.1), 19.5 (95% CI 15.5-23.4), and 22.5 (95% CI 15.7-29.4) for steady-state doses of 40, 160, and 320 mg/day, respectively; for haloperidol, -1.2 (95% CI
-4.1-1.7), 6.6 (95% CI 1.6-1-4.1-1.7), and 7.2 (95% CI 1.4-13.1) for steady-state doses of 2.5, 15, and 30 mg/day.
Although no patient in either treatment group experienced a QTc interval of 450 msec or greater, the QTc interval increased 30 msec or more in 11 and 17 ziprasidone-treated patients at 160 and 320 mg/day, respectively, and in 3 and 5 haloperidol-treated patients at 15 and 30 mg/day, respectively. Most treatment-emergent adverse drug reactions were mild in intensity, and none were severe.
CONCLUSION: The QTc interval in ziprasidone- and haloperidol-treated patients increased with dose.
Treatment with high doses of ziprasidone or haloperidol did not result in any patient experiencing a QTc interval of 450 msec or greater.
Pharmacotherapy. 2010 Feb;30(2):127-35. Effects of Oral Ziprasidone and Oral Haloperidol on QTc
interval in patients with Schizophrenia or Schizoaffective disorder. Miceli JJ, Tensfeldt TG, Shiovitz T,
Anziano R, O'Gorman C, Harrigan RH.
Abstract BACKGROUND: Antipsychotic agents have been associated with a prolonged QT interval. Data on the effects of ziprasidone and haloperidol on the QTc interval are lacking. OBJECTIVE: This study aimed to characterize the effects of 2 high-dose intramuscular injections of ziprasidone and haloperidol on the QTc interval at T(max). METHODS: This randomized, single-blind study enrolled patients with
schizophrenia or schizoaffective disorder in whom long-term antipsychotic therapy was indicated. Patients were randomized to receive 2 high-dose intramuscular injections of ziprasidone (20 and 30 mg) or
haloperidol (7.5 and 10 mg) separated by 4 hours. The primary outcome measure was the mean change from baseline in QTc at the T(max) of each injection. Each dose administration was followed by serial ECG and blood sampling for pharmacokinetic determinations. Twelve-lead ECG data were obtained immediately before and at predetermined times after injections. ECG tracings were read by a blinded central reader. Blood samples were obtained immediately before and after injections. Point estimates and 95% CIs for mean QTc and changes from baseline in QTc were estimated. No between-group hypothesis tests were conducted. For the assessments of tolerability and safety profile, patients underwent physical examination, including measurement of vital signs, clinical laboratory evaluation, and monitoring for adverse events (AEs) using spontaneous reporting. RESULTS: A total of 59 patients were assigned to treatment, and 58 received study medication (ziprasidone, 31 patients; haloperidol, 27; age range, 21-72 years; 79% male). After the
first injection, mean (95% CI) changes from baseline were 4.6 msec (0.4-8.9) with ziprasidone (n = 25) and 6.0 msec (1.4-10.5) with haloperidol (n = 24). After the second injection, these values were 12.8 msec (6.7-18.8) and 14.7 msec (10.2-19.2), respectively. Mild and transient changes in heart rate
and blood pressure were observed with both treatments. None of the patients had a QTc interval >480 msec. Two patients in the ziprasidone group experienced QTc prolongation >450 msec (457 and 454 msec) and QTc changes that exceeded 60 msec (62 and 76 msec) relative to the time-matched baseline values. With haloperidol, QTc interval values were <450 msec with no changes >60 msec. Treatment-emergent AEs were reported in 29 of 31 patients (93.5%) in the ziprasidone group and 25 of 27 patients (92.6%) in the haloperidol group; most events were of mild or moderate severity. Frequently reported AEs were
somnolence (90.3% and 81.5%, respectively), dizziness (22.6% and 7.4%), anxiety (16.1% and 7.4%), extrapyramidal symptoms (6.5% and 33.3%), agitation (6.5% and 18.5%), and insomnia (0% and 14.8%). CONCLUSIONS: In this study of the effects of high-dose ziprasidone and haloperidol in patients with
schizophrenic disorder, none of the patients had a QTc interval >480 msec, and changes from baseline
QTc interval were clinically modest with both drugs. Both drugs were generally well tolerated.
Clin Ther. 2010 Mar;32(3):472-91. Effects of high-dose ziprasidone and haloperidol on the QTc interval
after intramuscular administration: a randomized, single-blind, parallel-group study in patients with schizophrenia or schizoaffective disorder. Miceli JJ, Tensfeldt TG, Shiovitz T, Anziano RJ, O'Gorman C,
01/10/2010 18
Concetti pratici…
E’ da preferire/evitare una via IM ad una via IV?
Una minor biodisponibilità del farmaco riduce il rischio di
tossicità nelle somministrazioni estemporanee in PS.
Rischio che permane comunque modesto.
01/10/2010 19
Expert Opin Drug Saf. 2003 Nov;2(6):543-7.
Torsade de pointes associated with the administration of intravenous haloperidol:a review of the literature and practical guidelines for use.
Hassaballa HA, Balk RA.
Division of Pulmonary and Critical Care Medicine, Rush-Presbyterian St Luke's Medical Center, 1653 West Congress Parkway, Chicago, IL 60612, USA.
Abstract
Haloperidol is the most commonly used medication for the treatment of delirium and psychosis in the critically ill patient. Whilst generally considered to be safe, haloperidol has been associated with a
number of important cardiovascular side effects. The major toxicities include hypotension, cardiac
arrhythmias and prolongation of the corrected QT (QTc) interval. In particular, torsade de pointes, a
polymorphic ventricular tachyarrhythmia, has been associated with both intravenous and oral haloperidol administration. The management of torsade de pointes consists of discontinuation of the possible offending agent(s), correction of electrolyte abnormalities, administration of magnesium sulfate and, if necessary, overdrive pacing. Although clinicians should be aware of this potentially lethal complication of
intravenous haloperidol therapy, it should not deter clinicians from using intravenous haloperidol to treat acute agitation in the critically ill patient with a normal QTc.
J Hosp Med. 2010 Apr;5(4):E8-16.
The FDA extended warning for intravenous haloperidol and torsades de pointes: how should institutions respond?
Meyer-Massetti C, Cheng CM, Sharpe BA, Meier CR, Guglielmo BJ.
Department of Clinical Pharmacy, School of Pharmacy, University of California San Francisco, Medication Outcomes Center, San Francisco, California, USA. carla.meyer@unibas.ch
Abstract
BACKGROUND: In September 2007, the Food and Drug Administration (FDA) strengthened label
warnings for intravenous (IV) haloperidol regarding QT prolongation (QTP) and torsades de pointes (TdP) in response to adverse event reports. Considering the widespread use of IV haloperidol in the
management of acute delirium, the specific FDA recommendation of continuous electrocardiogram (ECG) monitoring in this setting has been associated with some controversy. We reviewed the evidence for the FDA warning and provide a potential medical center response to this warning.
METHODS: Cases of intravenous haloperidol-related QTP/TdP were identified by searching PubMed, EMBASE, and Scopus databases (January 1823 to April 2009) and all FDA MedWatch reports of haloperidol-associated adverse events (November 1997 to April 2008).
RESULTS: A total of 70 of IV haloperidol-associated QTP and/or TdP were identified. There were 54 reports of TdP; 42 of these events were reportedly preceded by QTP. When post-event QTc data were reported, QTc was prolonged >450 msec in 96% of cases. Three patients experienced sudden cardiac arrest.
Sixty-eight patients (97%) had additional risk factors for TdP/prolonged QT, most commonly receipt of concomitant proarrhythmic agents. Patients experiencing TdP received a cumulative dose of 5 mg to
645 mg, patients with QTP alone received a cumulative dose of 2 mg to 1540 mg.
CONCLUSIONS: While administration of IV haloperidol can be associated with QTP/TdP, this complication most often took place in the setting of concomitant risk factors. Importantly, the available data suggest
that a total cumulative dose of IV haloperidol of <2 mg can safely be administered without ongoing electrocardiographic monitoring in patients without concomitant risk factors.
01/10/2010 20
Concetti pratici…
L’effetto della politerapia con antipsicotici sul QT è
sinergico?
SI, sono potenzialmente sinergici sull’allungamento del
QT e quindi questi pazienti meritano più attenzione
Ann Gen Psychiatry. 2005 Jan 25;4(1):1.
QT interval prolongation related to psychoactive drug treatment: a comparison of monotherapy versus polytherapy.
Sala M, Vicentini A, Brambilla P, Montomoli C, Jogia JR, Caverzasi E, Bonzano A, Piccinelli M, Barale F, De Ferrari GM. Department of Health Sciences-Section of Psychiatry, IRCCS Policlinico S, Matteo, University of Pavia, School of Medicine, Pavia, Italy. michelasalacap@yahoo.it.
Abstract
BACKGROUND: Several antipsychotic agents are known to prolong the QT interval in a dose dependent manner. Corrected QT interval (QTc) exceeding a threshold value of 450 ms may be associated with an increased risk of life threatening
arrhythmias. Antipsychotic agents are often given in combination with other psychotropic drugs, such as antidepressants, that may also contribute to QT prolongation. This observational study compares the effects observed on QT interval between antipsychotic monotherapy and psychoactive polytherapy, which included an additional antidepressant or lithium treatment. METHOD: We examined two groups of hospitalized women with Schizophrenia, Bipolar Disorder and Schizoaffective Disorder in a naturalistic setting. Group 1 was composed of nineteen hospitalized women treated with antipsychotic
monotherapy (either haloperidol, olanzapine, risperidone or clozapine) and Group 2 was composed of nineteen hospitalized women treated with an antipsychotic (either haloperidol, olanzapine, risperidone or quetiapine) with an additional
antidepressant(citalopram, escitalopram, sertraline, paroxetine, fluvoxamine, mirtazapine, venlafaxine or clomipramine) or lithium. An Electrocardiogram (ECG) was carried out before the beginning of the treatment for both groups and at a second time after four days of therapy at full dosage, when blood was also drawn for determination of serum levels of the
antipsychotic.Statistical analysis included repeated measures ANOVA, Fisher Exact Test and Indipendent T Test.
RESULTS: Mean QTc intervals significantly increased in Group 2 (24 +/- 21 ms) however this was not the case in Group 1 (-1 +/- 30 ms) (Repeated measures ANOVA p < 0,01). Furthermore we found a significant difference in the number of patients
who exceeded the threshold of borderline QTc interval value (450 ms) between the two groups, with seven patients in Group 2 (38%) compared to one patient in Group 1 (7%) (Fisher Exact Text, p < 0,05).
CONCLUSIONS: No significant prolongation of the QT interval was found following monotherapy with an
antipsychotic agent, while combination of these drugs with antidepressants caused a significant QT prolongation.
Careful monitoring of the QT interval is suggested in patients taking a combined treatment of antipsychotic and antidepressant agents.
01/10/2010 21
Concetti pratici…
1.
Lo è anche con i farmaci antiaritmici?
2.
Assolutamente SI, i farmaci antiaritmici di classe terza
01/10/2010 22
Definizione della Sindrome del QT lungo
La sindrome da QT lungo (LQTS) è un
eterogeneo gruppo di disturbi congeniti o
acquisiti dei canali ionici coinvolti nella
ripolarizzazione.
E’ caratterizzata da un prolungamento
dell’intervallo QT all’ECG di superficie
e dalla
conseguente predisposizione a sviluppare
sincope e morte cardiaca improvvisa (SCD)
per causa aritmica.
Nella maggior parte dei casi l’exitus è
provocato da tachicardie ventricolari polimorfe
maligne chiamate “torsades de pointes” (TdP).
01/10/2010 23
Fattori di rischio per il QT lungo
Legati al paziente :
• Sindrome congenita del QT lungo
• Sesso femminile
• Bradicardia significativa, storia di
aritmie sintomatiche o altre
malattie cardiache
• Bilancio elettrolitico alterato
• Alterate funzioni renale o epatica
• Ipotirodismo
01/10/2010 24
Classificazione
Esistono diverse forme di LQTS:
congenite: canalopatie
(poche), interesse cardiologico
acquisite: iatrogene (molte),
interesse cardiologico e psichiatrico
È con il QT lungo cosa succede?
01/10/2010 25
L’allungamento dell’intervallo QT
può esacerbare una Triggered
activity, ossia la comparsa di
“post-potenziali" tipicamente
precoci.
Questi sono anormale oscillazioni
del potenziale di membrana che
seguono un potenziale d’azione. A
differenza dell’automaticità, i
post-potenziali dipendono dal
precedente potenziale d’azione (il
"trigger") e l’aritmia che ne risulta
mantiene una relazione con esso.
Torsione di punta, e adesso?
01/10/2010 26
O termina o innesca un rientro che
determina un fibrillazione ventricolare con
exitus del paziente se non defibrillata.
Quanto è grande il problema?
01/10/2010 27
Un QT marcatamente prolungato, spesso accompagnato da
torsioni di punta, può accadere nell’1-10% dei pazienti che
ricevono farmaci antiaritmici noti per prolungare il QT,
ma è
molto più raro nei pazienti che ricevono farmaci “non
cardiovascolari “ che potenzialmente prolungano il QT.
ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death
Il problema è principalmente correlato a farmaci cardiologici
che prolungano il QT per loro stesso meccanismo d’azione,
questi farmaci andrebbero iniziati in ambiente ospedaliero con
monitoraggio ECG
Problema limitato in psichiatria
01/10/2010 28
Abstract
BACKGROUND: Psychotropic drugs have the potential for QT interval prolongation, the
frequency is not known. The aim of this study was to monitor the occurrence of QT interval
prolongation in a non-selected population of patients treated with psychotropic drugs with
proarrhythmic potential.
METHODS: In consecutive patients hospitalized at psychotic wards at the Department of
Psychiatry treated with antipsychotic and antidepressant drugs with known or unexplored
proarrhythmic potential a 12-lead ECG was recorded (50 mm/s, 20 mm/mV) on therapy; the QT
interval was measured manually, corrected according to Bazett and Fridericia. QTc intervals of
470 ms (females) and 450 ms (males) were considered borderline, longer QTc intervals were
considered pathologic.
RESULTS: ECGs were recorded in 452 patients (187 females, 265 males, aged 43+/-16
years). Using Bazett's correction, abnormal QTc values were observed only in 2% of the whole
group and in 1.8% of the patients treated with drugs associated with QT prolongation (the
greatest QTc value is 490 ms in female and 480 ms in male). With Fridericia's correction, there
was only 1 case of borderline QTc in the whole group (the greatest QTc value is 450 ms in both
sex groups).
CONCLUSIONS: Our 2-year real-life experience shows that occurrence of QTc prolongation in
present psychiatric patients is low. Values associated with high risk of arrhythmias
(QTc>500 ms) were not observed. This might be related to the recent changes of spectrum of
antipsychotic therapy used, the general trend to use lower doses, and increasing awareness
about the drug-induced long QT syndrome.
Int J Cardiol. 2007 May 2;117(3):329-32. Epub 2006 Jul 24. Monitoring of QT interval in patients treated with psychotropic drugs. Novotny T, Florianova A, Ceskova E, Weislamplova M, Palensky V, Tomanova J, Sisakova M, Toman O, Spinar J.
Abstract
Although intravenous haloperidol (HAL) is an effective medication that is often prescribed to
treat agitation, several instances of torsade de pointes or prolonged QT interval have been
reported. To investigate the association between intravenous HAL and QT prolongation and
between intravenous HAL and ventricular tachyarrhythmia, a cross-sectional cohort study was
performed that included measuring corrected QT intervals (QTc) on an emergency basis before
intravenous HAL and continuously monitoring electrocardiographic (ECG) findings after
intravenous HAL. During a 2-month period, 47 patients received intravenous injections to
control psychotic disruptive behavior. According to clinical practice, patients were divided as
follows. The FZ-alone group was treated with intravenous flunitrazepam (FZ), and the
FZ-plus-HAL group received intravenous FZ followed by intravenous FZ-plus-HAL. Although the difference in the
mean QTc immediately after intravenous FZ between the two groups was not significant, the
mean QTc after 8 hours in the FZ-plus-HAL group was longer than that in the FZ-alone group (p
< 0.001). Four patients in the FZ-plus-HAL group had a QTc of more than 500 msec after 8
hours. The change in QTc during 8 hours significantly differed between the two groups (t = 2.64,
p > 0.05). Furthermore, the change in QTc was moderately correlated with the dose of
intravenous HAL, as evidenced by a coefficient of correlation of 0.48 (p < 0.001). However,
ventricular tachyarrhythmia was not detected among 307 patients within a 1-year period,
although the ECG was continuously monitored for at least 8 hours after intravenous HAL. The
modest nature of QTc prolongation and the apparent absence of ventricular tachyarrhythmia
under continuous ECG monitoring indicate that QTc prolongation associated with intravenous
HAL is not necessarily dangerous. However, in an emergency situation, clinicians cannot
exclude patients predisposed to torsade de pointes, such as those with inherited ion channel
disorders. Therefore, clinicians should be aware of the association between intravenous HAL
and QT prolongation.
J Clin Psychopharmacol. 2001 Jun;21(3):257-61.The association between intravenous haloperidol and prolonged QT interval. Hatta K, Takahashi T, Nakamura H, Yamashiro H, Asukai N, Matsuzaki I, Yonezawa Y. Department of Psychiatry, Tokyo Metropolitan Bokuto General Hospital, Japan. hattak8s@cd.mbn.or.jp
Abstract BACKGROUND: Antipsychotic agents have been associated with a prolonged QT interval. Data on
the effects of ziprasidone and haloperidol on the QTc interval are lacking. OBJECTIVE: This study aimed to characterize the effects of 2 high-dose intramuscular injections of ziprasidone and haloperidol on the QTc interval at T(max). METHODS: This randomized, single-blind study enrolled patients with schizophrenia or schizoaffective disorder in whom long-term antipsychotic therapy was indicated. Patients were randomized to receive 2 high-dose intramuscular injections of ziprasidone (20 and 30 mg) or haloperidol (7.5 and 10 mg) separated by 4 hours. The primary outcome measure was the mean change from baseline in QTc at the T(max) of each injection. Each dose administration was followed by serial ECG and blood sampling for pharmacokinetic determinations. Twelve-lead ECG data were obtained immediately before and at
predetermined times after injections. ECG tracings were read by a blinded central reader. Blood samples were obtained immediately before and after injections. Point estimates and 95% CIs for mean QTc and changes from baseline in QTc were estimated. No between-group hypothesis tests were conducted. For the assessments of tolerability and safety profile, patients underwent physical examination, including
measurement of vital signs, clinical laboratory evaluation, and monitoring for adverse events (AEs) using spontaneous reporting. RESULTS: A total of 59 patients were assigned to treatment, and 58 received study medication (ziprasidone, 31 patients; haloperidol, 27; age range, 21-72 years; 79% male). After the first injection, mean (95% CI) changes from baseline were 4.6 msec (0.4-8.9) with ziprasidone (n = 25) and 6.0 msec (1.4-10.5) with haloperidol (n = 24).After the second injection, these values were 12.8 msec (6.7-18.8) and 14.7 msec (10.2-19.2), respectively. Mild and transient changes in heart rate and blood pressure were observed with both treatments. None of the patients had a QTc interval >480 msec. Two patients in the ziprasidone group experienced QTc prolongation >450 msec (457 and 454 msec) and QTc changes that exceeded 60 msec (62 and 76 msec) relative to the time-matched baseline values. With haloperidol, QTc interval values were <450 msec with no changes >60 msec. Treatment-emergent AEs were reported in 29 of 31 patients (93.5%) in the ziprasidone group and 25 of 27 patients (92.6%) in the haloperidol group; most events were of mild or moderate severity. Frequently reported AEs were somnolence (90.3% and 81.5%, respectively), dizziness (22.6% and 7.4%), anxiety (16.1% and 7.4%), extrapyramidal symptoms (6.5% and 33.3%), agitation (6.5% and 18.5%), and insomnia (0% and 14.8%).CONCLUSIONS: In this study of the effects of high-dose ziprasidone and haloperidol in patients with schizophrenic disorder, none of the patients
had a QTc interval >480 msec, and changes from baseline QTc interval were clinically modest with both drugs. Both drugs were generally well tolerated.
Clin Ther. 2010 Mar;32(3):472-91. Effects of high-dose ziprasidone and haloperidol on the QTc interval after intramuscular administration: a randomized, single-blind, parallel-group study in patients with schizophrenia or schizoaffective disorder. Miceli JJ, Tensfeldt TG, Shiovitz T, Anziano RJ, O'Gorman C, Harrigan RH.
Farmaci che frequentemente prolungano il QT
01/10/2010 29
ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death
ALOPERIDOLO
01/10/2010 30
antagonista dopaminergico non
selettivo
+
AMIODARONE
01/10/2010 31
Effetto principale:
- blocco canali IKr (correnti del potassio rapide) e corrente IKs
(correnti del potassio lente).
- Altri effetti sono blocco dei canali per il sodio (classe Ia), del
calcio e fungere da beta-bloccante (classe II).
Meccanismo: Il blocco dei canali per i potassio comporta una
incapacità da parte della cellula miocardica di ritornare nei tempi
fisiologici al potenziale di riposo; in particolare, viene ad essere
prolungato il periodo refrattario, condizione che comporta un
impedimento elettrico nella genesi di nuovi potenziale d'azione
nelle cellule con bassa soglia di eccitabilità, con conseguente
marcato effetto anti-aritmico. tale fenomeno è testimoniato nella
pratica clinica dal prolungamento dell'intervallo QT.
SOTALOLO
01/10/2010 32
Beta bloccante non selettivo
+
01/10/2010 33
Farmaci con rischio di TDP
Un paziente “vero” della cardiologia, UCIC,
rianimazione o medicina generale…
Anziano con infezione respiratoria, in FA cronica, con
agitazione psicomotoria (notturna).
E’ sotto cordarone (FA), ha iniziato la claritromicina
da tre giorni, e nella notte diamo il Serenase iv…
Nuovi farmaci confronti
01/10/2010 35
Curr Drug Saf. 2010 Jan;5(1):97-104. QT alterations in psychopharmacology: proven candidates and
suspects. Alvarez PA, Pahissa J. Department of Internal Medicine, CEMIC, Buenos Aires, Argentina. palvarez@cemic.edu.ar
Abstract
Psychotropics are among the most common causes of drug induced acquired long QT
syndrome. Blockage of Human ether-a-go-go-related gene (HERG) potassium channel by
psychoactive drugs appears to be related to this adverse effect. Antipsychotics such as
haloperidol, thioridazine, sertindole, pimozide, risperidone, ziprasidone, quetiapine,
olanzapine and antidepressants such as amitriptyline, imipramine, doxepin, trazadone,
fluoxetine depress the delayed rectifier potassium current (IKr) in a dose dependent
manner in experimental models. The frequency of QTc prolongation (more than 456 ms)
in psychiatric patients is estimated to be 8%. Age over 65 years, tricyclic antidepressants
(TCA), thioridazine, droperidol, olanzapine, and higher antipsychotic doses were predictors of
significant QTc prolongation. In large epidemiological controlled studies a dose dependent
increased risk of sudden death has been identified in current users of antipsychotics
(conventional and atypical) and of TCA. Thioridazine and haloperidol shared a similar
relative risk of SCD. Lower doses of risperidone had a higher relative risk than
haloperidol for cardiac arrest and ventricular arrhythmia. No increased risk was identified in
current users of selective serotonin reuptake inhibitors (SSRI). Cases of TdP have been
reported with thioridazine, haloperidol, ziprazidone, olanzapine and TCA.
Evidence of QTc
prolongation with sertindole is significant and this drug has not been approved by the
Food and Drugs Administration (FDA). A large trial is ongoing to evaluate the cardiac risk
profile of ziprazidone and olanzapine.
Selective serotonin reuptake inhibitors have been
associated with QTc prolongation but no cases of TdP have been reported with the use of these
agents. There are no reported cases of lithium induced TdP. Risk factors for drug induced LQT
syndrome and TdP include: female gender, concomitant cardiovascular disease, substance
abuse, drug interactions, bradychardia, electrolyte disorders, anorexia nervosa, and congenital
Long QT syndrome. Careful selection of the psychotropic and identification of patient's risk
factors for QTc prolongation is applicable in current clinical practice.
Raccomandazioni specifiche del AIFA
Sull’utilizzo di:
Serenase
Droperidolo
Primozide
Raccomandazioni
01/10/2010 37
ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death
Il mio paziente ha il QT lungo,
cosa faccio?
01/10/2010 38
1-
sospensione dei farmaci implicati nell’allungamento del tratto QT;
2- il mantenimento di livelli di concentrazione di K+ plasmatici tra 4 – 4,5
mmol/L;
3- la somministrazione di 1 – 2 g di solfato magnesio EV, con possibilità di
aumentare la dose e la velocità d’infusione in base alla gravità del quadro
clinico;
4- in caso di refrattarietà al trattamento e di concomitante bradicardia, può
essere d’aiuto il “pacing cardiaco temporaneo” o l’isoproterenolo.
LINEE GUIDA PER IL TRATTAMENTO CON
FARMACI A POTENZIALE RISCHIO DI
ALLUNGAMENTO DEL QTC
Pazienti a basso rischio (QTc basale 0.41 sec): non
necessitano di ECG dopo l’introduzione di un singolo antipsicotico
in monoterapia. Necessario ECG di controllo per farmaci associati
all’antipsicotico con potenziale aumento del QT
Pazienti borderline (QTc 0.42-0.44.sec): sono a basso rischio di
aritmia. Necessitano di un ECG dopo la prima dose e allo steady
state. Se QTc >450 ms ridurre i dosaggi o cambiare con un
farmaco meno a rischio. ECG di controllo per polifarmacoterapie.
Pazienti ad alto rischio (QTc >0.45 sec) Sono ad alto rischio di
aritmie necessitano di un ECG dopo la prima dose e allo steady
state. Se QTc >500 ms cambiare con farmaco meno a rischio.
ECG di controllo per polifarmacoterapie. Monitoraggio degli
elettroliti
Moss AJ, Zareba W, Benhorin J, et al. ISHNE guidelines for electrocardiographic evaluation of drug-related QT prolongation and other alterations in ventricular repolarization: Task force summary. A report of the Task Force of the International
Society for Holter and Noninvasive Electrocardiology (ISHNE), Committee on Ventricular Repolarization. Ann Noninvasive Electrocardiol 2001;6:333–341
Livello di
rischio Definizione Screening ECG Follow-up ECG Consulenza cardiologica Monitoraggio sec. Holter
Molto
basso Maschi senza fattori di rischio necessario Non necessario Non necessariaNon Non necessario Basso Donne senza fattori di rischio necessario Non necessario Non necessariaNon Non necessario Medio Patologie cardiache Consigliabile Consigliabile Consigliabile Non necessario Alto Interazioni tra farmaci Necessario Necessario Necessaria Discutibile Molto alto Storia di LQTS Obbligatorio Obbligatorio Obbligatoria Obbligatorio
Approccio clinico e strumentale in base al
livello di rischio.
Viskin S. Long QT syndrome caused by non-cardiac drugs. Progress in Cardiovascular Disease. 2003; 45:415-427.
01/10/2010 41
Il farmaco che sto dando
prolunga il QT?
www.qtdrugs.org
www.torsades.org
Su questi siti si trova una lista
sempre aggiornata dei
farmaci che possono
prolungare il QT
E il QT corto?
01/10/2010 42
La sindrome del QT breve è una patologia
ereditaria a carattere autosomico dominante
Si caratterizza per la presenza sull’ecg di
base di un intervallo QT spiccatamente
breve ed una propensione a sviluppare
aritmie ipercinetiche a livello atriale e/o
ventricolare in assenza di anomalie
01/10/2010 43
ECG QT corto
• Intervallo QT breve,
genericamente ≤ 300 ms, che non
cambia in maniera significativa
con il ritmo cardiaco.
• Si possono notare in oltre onde
T alte ed appuntite.
• Alcuni individui possono anche
presentare fibrillazione atriale
01/10/2010 44
Basi genetiche
Basi genetiche della Short QT Syndrome
Wilde AAM e Coll. Heart 2005;91:1352-1358
Le mutazioni nei geni KCNH2, KCNJ2 e
KCNQ1. Questi geni codificano le
01/10/2010 45
Trattamento
Al momento l’unica azione terapeutica efficace
per i soggetti affetti da sindrome del QT breve
è l’impianto di un defibrillatore automatico.
Trattamento mediante AICD
• L’unica “copertura” sicuramente efficace nei
pazienti considerati ad alto rischio, in rapporto
anche alla difficile valutazione della efficacia
farmacologica
• Sono stati segnalati diversi casi di “Shock
inappropriato da doppio conteggio includente
una onda T di elevato voltaggio
Trattamento
Un suggerimento da cardiologo:
Provate a dare l’aloperidolo…. magari si
allunga il QT e risparmiamo un defi…!
Commenti conclusivi
Il QT lungo esiste nella misura in cui lo si misura. L’occhio del cardiologo
quasi non vede un QT <500msec, mentre l’elettrocardiografo misura
variazioni anche “impercettibili” che spesso corrispondono
all’allungamento massimo che questi farmaci possono causare (40msc)
sono sempre poi un quadratino da 1 mm…
Gli effetti cardiotossici avvengono quasi sempre in pazienti cardiopatici,
con farmaci antiaritmici, in politerapia o con disturbi elettrolitici.
Quando vi arriva un referto ECG con diagnosi di QT lungo, spesso è già
soppesato dal cardiologo. Il significato è = sospendi il farmaco.
Non sottovalutare il QT lungo, ma valutalo insieme al cardiologo.
Le dimostrazioni del nesso tra l’allungamento del QT e la morte cardiaca
sono note ma l’incidenza (NNT - NNH) è poco conosciuta poiché molto
bassa. Infatti, le torsioni di punta da antipsicotico sono molto molto rare.
01/10/2010 47
La riflessione di un cardiologo
Il possibile rischio cardiologico conferito da questi farmaci
è comunque MINORE del sicuro effetto dei fattori di
rischio convenzionali tra i quali il fumo, sedentarietà, il
sovrappeso e l’ipertensione o della sindrome
metabolica spesso presenti nei pazienti psichiatrici.
Grazie dell’attenzione
01/10/2010 49
